Insulin-like growth factor-II is increased in systemic sclerosis-associated pulmonary fibrosis and contributes to the fibrotic process via Jun N-terminal kinase- and phosphatidylinositol-3 kinase-dependent pathways

被引:46
作者
Hsu, Eileen [1 ]
Feghali-Bostwick, Carol A. [1 ,2 ]
机构
[1] Univ Pittsburgh, Sch Med, Div Pulmm Allergy & Crit Care Med, Pittsburgh, PA 15213 USA
[2] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15213 USA
关键词
D O I
10.2353/ajpath.2008.071021
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
Systemic sclerosis (SSc)-related pulmonary fibrosis, for which there are few effective therapies, is the most common cause of SSc-related mortality. We examined insulin-like growth factor (IGF)-II expression in explanted lung tissues from control and SSc patients to determine its role in the pathogenesis of fibrosis. IGF-II levels in vivo were detected using immunohistochemistry. Primary lung fibroblasts were cultured from lung tissues, and IGF-II mRNA was measured using reverse transcriptase-polymerase chain reaction. Western blot analysis measured extracellular matrix (ECM) production and phosphorylated signaling molecules. Immunostaining revealed increased IGF-II expression in fibroblastic foci of SSc lungs. Furthermore, primary SSc lung fibroblasts had a fourfold increase in IGF-II mRNA and a twofold increase in IGF-II protein compared with normal lung fibroblasts. IGF-II mRNA in SSc lung fibroblasts was expressed primarily from the P3 promoter of the IGF-H gene, and IGF-II induced both a dose- and time-dependent increase in collagen type I and fibronectin production. IGF-H triggered the activation of both phosphatidyhnositol-3 kinase and Jun N-terminal kinase signaling cascades, the inhibition of which diminished IGF-II-induced ECM production. Our study demonstrates increased local IGF-II expression in SSc-associated pulmonary fibrosis both in vitro and in vivo as well as IGF-II-induced ECM production through both phosphatidyhnositol-3 kinase- and Jun N-terminal kinase-dependent pathways. our results provide novel insights pulmonary fibrosis.
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页码:1580 / 1590
页数:11
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